# Whole-genome CRISPR screening identifies genetic manipulations to reduce immune rejection of stem cell-derived islets

Article · Sintov E, Nikolskiy I, Barrera V, Hyoje-Ryu Kenty J, Atkin AS, Gerace D, Ho Sui SJ, Boulanger K, Melton DA

- Archive id: doi:10.1016/j.stemcr.2022.08.002
- Published: 2022-09-01
- Venue: Stem cell reports
- DOI: https://doi.org/10.1016/j.stemcr.2022.08.002
- PMID: 36055241
- PMCID: PMC9481918
- Citations: 42
- Source URL: https://doi.org/10.1016/j.stemcr.2022.08.002
- PDF: https://europepmc.org/articles/PMC9481918/pdf
- Provenance: europepmc

## Abstract

Human embryonic stem cells (hESCs) provide opportunities for cell replacement therapy of insulin-dependent diabetes. Therapeutic quantities of human stem cell-derived islets (SC-islets) can be produced by directed differentiation. However, preventing allo-rejection and recurring autoimmunity, without the use of encapsulation or systemic immunosuppressants, remains a challenge. An attractive approach is to transplant SC-islets, genetically modified to reduce the impact of immune rejection. To determine the underlying forces that drive immunogenicity of SC-islets in inflammatory environments, we performed single-cell RNA sequencing (scRNA-seq) and whole-genome CRISPR screen of SC-islets under immune interaction with allogeneic peripheral blood mononuclear cells (PBMCs). Data analysis points to "alarmed" populations of SC-islets that upregulate genes in the interferon (IFN) pathway. The CRISPR screen in vivo confirms that targeting IFNγ-induced mediators has beneficial effects on SC-islet survival under immune attack. Manipulating the IFN response by depleting chemokine ligand 10 (CXCL10) in SC-islet grafts confers improved survival against allo-rejection compared with wild-type grafts in humanized mice. These results offer insights into the nature of immune destruction of SC-islets during allogeneic responses and provide targets for gene editing.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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